The eye surface is kept moist by a tear film composed of an oily layer, a watery layer and a layer of mucus. The outermost oily layer is produced by the meibomian glands and reduces tear evaporation. The middle layer is the watery liquid typical of tears and is produced by lacrimal glands. The inner layer of mucus is produced by goblet cells in the conjunctiva, and enables the watery layer to evenly coat the eye. Mucins are the main component of mucus and have an important role in maintaining the aqueous and oily layers of the eye film.
Dry eye (keratoconjunctivitis sicca or keratitis sicca) is a chronic dryness of the corneal and conjunctival surfaces and results from a decrease in the production of tear components or from an altered ratio of the individual oil, water and mucus components to each other. People with dry eye have various symptoms including redness, soreness, burning, itching, photophobia, blurred vision, foreign body sensation (grittiness) and contact lens intolerance. Environmental conditions can worsen these symptoms.
Dry eye can be a side effect caused by certain drugs such as diuretics, beta blockers, antihistamines, sleeping pills, or pain relievers. The LASIK (laser assisted in situ keratomileusis) procedure can cause dry eye due to corneal denervation (Toda, 2007). Several hormones impact tear component production and hormone insufficiency can cause dry eye (Sullivan, 2004). The prevalence of dry eye increases with age and is higher among women (Moss et al. 2000).
Dry eye can be classified as either tear production deficient or evaporative dry eye (Lemp, 1995). The former includes Sjogren-associated and non-Sjogren associated dry eye. Sjogren's disease is an autoimmune syndrome of the exocrine glands that includes dry eyes and dry mouth (Srinvassan and Siomovic, 2007). In both of these conditions, there is an inflammatory environment characterized by T cell infiltration of the conjunctiva, and increased levels of the inflammatory cytokines tumor necrosis factor (TNF), interleukin 1 alpha (IL-1a), IL-6, IL-8 and IL-10 (Zoukhri, 2006). These factors result in alterations of the conjunctival epithelia, a loss of goblet cells and a decrease in mucin production.
Current therapies for dry eye include the use of artificial tears to rehydrate the ocular surface and provide symptomatic relief. Their benefits are short lived, however, and frequent dosing is required. Other therapies include steroids (U.S. Pat. No. 5,958,912), cyclosporine A (Tauber, 1998), hydroxyeicosatetraenoic acid derivatives (U.S. Pat. No. 5,696,166), adenine analogues (Jumblatt and Jumblatt, 1998), purinergic receptor antagonists (U.S. Pat. No. 5,900,407), phosphodiesterase inhibitors (U.S. Pat. No. 4,753,945), glycosides (U.S. Pat. No. 7,223,737), melanocyte stimulating hormones (U.S. Pat. No. 4,868,154), and conjugated estrogens (U.S. Pat. No. 5,041,434).
Goblet cells are the primary source of excreted mucin. The cornea and conjunctival epithelial cells also produce transmembrane mucin to maintain a hydrated surface. Lacrimal cells produce a small soluble mucin. Dry eye causes changes in both the secreted and membrane-associated mucins (Gipson et al. 2004). Release of mucin from conjunctival cells is regulated by neurotransmitters.
There is an interest in treating dry eye with agents that can increase mucin production. Nicotinic receptor agonists have been reported to stimulate conjunctival cells to secrete mucin (U.S. Pat. No. 6,277,855). The purinoreceptor P2Y2 agonist INS365 increased goblet cell density in a rat model of dry eye (Fujihara et al., 2001). Some anti-ulcer drugs stimulate mucus secretion. The anti-ulcer drug gefarnate increases conjunctival goblet cell density in a rabbit model of dry eye (Nakamura et al. 1998). Hormone replacement therapy for post-menopausal women causes an increase in conjunctival goblet cell density (Pelit et al. 2003). Cyclosporine treatment results in an increase in goblet cell numbers in patients with dry eye (Kunert et al. 2002).
As goblet cells are present in other tissues (digestive and respiratory epithelia; agents that increase mucin production may have additional utilities in treating conditions such as constipation, anorexia, dry mouth (xerostomia) and respiratory pathologies (Shimotoyodome et al., 2000; Deplancke and Gaskins, 2001).